MDMA is a serotonin neurotoxin that selectively destroys the fine fibers originating in the dorsal raphe nucleus. We conducted a preliminary study to verify that MDMA decreases the serotonergic innervation of the hypothalamus and to determine the effect of MDMA on behavior and biogenic amines in the cerebral spinal fluid (CSF). Juvenile male monkeys were pair housed and observed for 2 weeks prior to drug (n=2) or vehicle treatment (n=2). They were then observed during the 4 day treatment period and for the following 2 weeks. CSF samples were obtained during each period and the brains were obtained for serotonin fiber staining at the end of the observation period. MDMA caused marked change in several behavioral parameters including proximity, passivity, locomote,self grooming, hairpluck, and social contact. In contrast, grooming and mounting increased during the post-drug period. From the changes in CSF biogenic amines, it appeared that one monkey responded more acutely than the other to the drug. There was a significant increase in CSF serotonin during and after drug treatment in one monkey. The same monkey showed a decrease in the major metabolite of serotonin, 5-hydroxyindoleacetic acid (5HIAA) and in the major metabolite of dopamine, homovanillic acid (HVA) during drug treatment. Immunohistochemical staining of the serotonin fibers in the hypothalamus has been completed and the computer assisted image analysis is ongoing. There appears to be a decrease in serotonin fibers in the responding monkey compared to the saline injected controls; however, quantitation is required. We are using the skeletonizing feature of NIH Image to determine the number of pixels covered by fibers as a means of quantitation of serotonergic innervation of the hypothalamus. These very preliminary data suggest that (1) monkeys exhibit an individual sensitivity to MDMA neurotoxicity and that a higher dose of drug is needed to obtain consistent responses between monkeys; (2) there is an initial and long-lasting dumping of serotonin into the CSF which accompanies fiber degradation; (3) there appears to be a reduction of fine fiber innervation of the hypothalamus; (4) there are marked behavioral changes induced by MDMA, some of which are manifested during drug treatment and some of which are a later consequence of drug treatment; (5) this model provides a noninvasive method of specifically lesioning the dorsal raphe and it will be useful to determine the neuroendocrine consequences of specific lesions in the dorsal raphe innervation of the hypothalamus. We intend to pursue the effect of MDMA lesions on the serotonergic regulation of prolactin secretion with the next competitive renewal of grant HD17269.